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Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide
Authors:
Claudine
Bisson
(University of Sheffield)
,
K. Linda
Britton
(University of Sheffield)
,
Svetlana E.
Sedelnikova
(University of Sheffield)
,
H. Fiona
Rodgers
(University of Sheffield)
,
Thomas C.
Eadsforth
(University of Dundee)
,
Russell C.
Viner
(Syngenta)
,
Tim R.
Hawkes
(Syngenta)
,
Patrick J.
Baker
(University of Sheffield)
,
David W.
Rice
(University of Sheffield)
Co-authored by industrial partner:
Yes
Type:
Journal Paper
Journal:
Angewandte Chemie International Edition
, VOL 55
, PAGES 13485 - 13489
State:
Published (Approved)
Published:
October 2016
Diamond Proposal Number(s):
7423
,
1218

Abstract: Programs of drug discovery generally exploit one enantiomer of a chiral compound for lead development following the principle that enantiomer recognition is central to biological specificity. However, chiral promiscuity has been identified for a number of enzyme families, which have shown that mirror-image packing can enable opposite enantiomers to be accommodated in an enzyme's active site. Reported here is a series of crystallographic studies of complexes between an enzyme and a potent experimental herbicide whose chiral center forms an essential part of the inhibitor pharmacophore. Initial studies with a racemate at 1.85 Å resolution failed to identify the chirality of the bound inhibitor, however, by extending the resolution to 1.1 Å and by analyzing high-resolution complexes with the enantiopure compounds, we determined that both enantiomers make equivalent pseudosymmetric interactions in the active site, thus mimicking an achiral reaction intermediate.
Journal Keywords: chirality; drug design; enantioselectivity; inhibitors; structural biology
Subject Areas:
Chemistry,
Biology and Bio-materials,
Medicine
Instruments:
I02-Macromolecular Crystallography
,
I03-Macromolecular Crystallography
,
I04-Macromolecular Crystallography
Documents:
Bisson_et_al-2016-Angewandte_Chemie_International_Edition.pdf